Prostate cancer remains an incredibly important problem for patients in the United States. In general there are three important questions that face men with the disease. Men must determine if their cancer warrants active treatment at time of diagnosis. If treatment is warranted which treatment is better for the patient, radical prostatectomy (RP) or external beam radiotherapy (EBRT) or brachytherapy? Finally if the patient develops metastatic disease how best one should be treated? Although the majority of this project is focused on men with recurrent cancer through a strong multi-disciplinary collaboration we are also working on learning more about the need for treatment and the outcome of patients with newly diagnosed prostate cancer. I had previously shown that the combination of docetaxel and thalidomide had activity in treating castrate-resistant prostate cancer (CRPC). I hypothesized that the addition of a second antiangiogenic agent with a different target could increase the activity of this combination. Thus a series of preclinical studies in support of this trial were conducted by Dr. William Figg (GMB, CCR) to better delineate the antiangiogenic targets of thalidomide. In microarray experiments using thalidomide and thalidomide analogs, which are similar to the active metabolite of thalidomide, multiple angiogenesis factors (KIF5A, TTK, etc.) were downregulated, but not vascular endothelial growth factor (VEGF). VEGF expression was not altered in xenograft experiments using these analogs; however, platelet-derived growth factor was significantly reduced. Bevacizumab is a recombinant humanized antiVEGF mAb composed of human IgG1 framework regions and antigen-binding complementary determining regions from a murine mAb which blocks the binding of human VEGF receptors. It has no known significant activity against other targets. My hypothesis was that by combining the antiVEGF activity of bevacizumab with the antiangiogenic activity of thalidomide against multiple targets, but not VEGF, I could effectively suppress the most important angiogenic factors, leading to increased antitumor activity. The treatment regimen consisted of docetaxel 75 mg/m2 plus bevacizumab 15 mg/kg on day 1 every 21 days, plus daily thalidomide 200 mg and prednisone 10 mg. All 60 patients enrolled as planned. The median Gleason score was 8, on-study PSA 99 ng/mL (range, 6.0 to 4399), and prestudy PSA doubling time (PSADT) was. 1.6 months. The PSA decline rate and time to progression (18 months) was the most of active of any published regimen. More recently we have conducted a similar trial using lenalidomide instead of thalidomide as a means to decrease toxicity. To date all of the planned 62 patients have been enrolled with similar clinical activity. Yet despite this encouraging activity of these regimens these combinations are unlikely to be tested in the near future by the cooperative groups due in part to the failure of the individual components to show meaningful activity when combined with docetaxel. Cabozantinib is a potent inhibitor of multiple receptor tyrosine kinases including c-Met, vascular endothelial growth factor receptor 2 (VEGFR2) and RET. In both in vivo and in vitro studies, cabozantinib has shown activity in prostate cancer. We hypothesized that addition of cabozantinib to docetaxel and prednisone, in patients with mCRPC, would have an acceptable toxicity profile and potentially minimize tumor resistance and could lead to improved survival by targeting different cellular pathways simultaneously. We conducted a phase I trial to determine the safety profile and the recommended phase II dose of cabozantinib in combination with docetaxel and prednisone. Patients received a fixed dose of docetaxel (75 mg/m2 IV day 1 of each 21 day cycle and prednisone (5 mg po q12 hours) in combination with cabozantinib at three escalating doses. Dose level 1 was 20 mg po qdaily, dose level 2 was 40 mg po qdaily, and dose level 3 was 60 mg po daily. Using a standard 3 + 3 design, a MTD has been defined and initial results demonstrate a striking PFS compared to published data in this population. Secondary objectives include assessments of pharmacokinetics of each agent, evaluation of antitumor activity of the combination therapy, and assessment of changes in molecular biomarkers in the pathways of receptor tyrosine kinases and angiogenesis, as well as the biomarkers for bone metabolism. Restaging with bone and CT scan will be undertaken every 3 cycles. To date the study has had the expected toxicities with an impressive progression free survival (PFS) in the patients treated to date. Additional patients and a randomized study (approved by CTEP) will be needed to determine if multi-pathway blockade in combination with docetaxel is meaningful in men with mCRPC. In collaboration with the LTIB (Jeff Schlom) we have attempted to translate immunologic work into the clinic. We had previously reported the clinical results of a Phase I trial combining ipilimumab with a vaccine containing transgenes for prostate-specific antigen (PSA) and for a triad of costimulatory molecules PROSTVAC in patients with metastatic castration-resistant prostate cancer. Thirty patients were treated with escalating ipilimumab and a fixed dose of vaccine. Associations between overall survival and immune cell subsets prior to treatment, and the change in a given immune cell subset 70 days post-initiation of therapy, were evaluated and trends were noted towards associations for longer overall survival with several immune subsets. These results should be considered as hypothesis generating and should be further evaluated in larger immunotherapy trials as potential markers of outcome. Finally we have completed several trials combining vaccines not only with check point inhibitors such as ipilimumab but with hormonal agents and chemotherapy. Currentley we are combining PROSTVAC with the potent AR antagonist in 2 populations with encouraging early results. The ultimate goal of my program is to improve the outcome of patients with prostate cancer. I have helped better defined measures of outcome and am now working to characterize genetic markers that may help us select appropriate therapy for patients.